rs1554305719

Variant names:

• chr7-16278175-TTGTTATCTTCTTC-T
• rs1554305719
• NM_001101426.4:c.874_886delGAAGAAGATAACA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001101426.4(CRPPA):​c.874_886delGAAGAAGATAACA​(p.Glu292AsnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E292E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRPPA NM_001101426.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.13
• Publications: 0 publications found

Genes affected

CRPPA (HGNC:37276): (CDP-L-ribitol pyrophosphorylase A) This gene encodes a 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase-like protein. Mutations in this gene are the cause of Walker-Warburg syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

CRPPA Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• myopathy caused by variation in CRPPA

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2U

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy without intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-16278175-TTGTTATCTTCTTC-T is Pathogenic according to our data. Variant chr7-16278175-TTGTTATCTTCTTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 473159.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRPPA	NM_001101426.4	c.874_886delGAAGAAGATAACA	p.Glu292AsnfsTer3	frameshift_variant	Exon 6 of 10	ENST00000407010.7	NP_001094896.1
CRPPA	NM_001368197.1	c.769_781delGAAGAAGATAACA	p.Glu257AsnfsTer3	frameshift_variant	Exon 5 of 9		NP_001355126.1
CRPPA	NM_001101417.4	c.724_736delGAAGAAGATAACA	p.Glu242AsnfsTer3	frameshift_variant	Exon 5 of 9		NP_001094887.1
CRPPA	NR_160656.1	n.939_951delGAAGAAGATAACA		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRPPA	ENST00000407010.7	c.874_886delGAAGAAGATAACA	p.Glu292AsnfsTer3	frameshift_variant	Exon 6 of 10	5	NM_001101426.4	ENSP00000385478.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7;C5190987:Autosomal recessive limb-girdle muscular dystrophy type 2U Pathogenic:1

Jul 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with ISPD-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 473159). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu292Asnfs*3) in the ISPD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ISPD are known to be pathogenic (PMID: 23288328). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554305719; hg19: chr7-16317800;